Endoplasmic reticulum stress responses in Leishmania

Abstract

Perturbation of endoplasmic reticulum (ER) homeostasis can lead to an accumulation of misfolded proteins within the ER lumen causing initiation of ER stress. To reestablish homeostasis and mitigate the stress, a series of adaptive intracellular signaling pathways termed the unfolded protein response (UPR) are activated. ER stress is of considerable interest to parasitologists because it takes place in parasites subjected to adverse environmental conditions. During a digenetic lifestyle, Leishmania parasites encounter and adapt to harsh environmental conditions that provide potential triggers of ER stress. These include nutrient deficiency, hypoxia, oxidative stress, changing pH, and shifts in temperature. Protozoan human pathogens, including the causative agents of trypanosomiasis, leishmaniasis, toxoplasmosis and malaria, contain a minimal conventional UPR network relative to higher eukaryotic cells. Three different signaling pathways in the ER stress response have been described in trypanosomatids: these pathways involve (i) the down-regulation of translation by a protein kinase RNA-like ER kinase (PERK), (ii) the ER-associated degradation (ERAD) pathway, and (iii) the spliced leader silencing (SLS) pathway and its target mRNAs. Under short-term ER stress, signaling from PERK activates autophagy, a cell survival response. But both chronic and unresolved ER stresses lead to initiation of apoptotic events and eventual cell death. This review presents the current understanding of the ER stress response in Leishmania with an emphasis on protein folding and ER quality control, unfolded protein response, autophagy as well as apoptosis in reference to the mammalian system.

Keywords: Autophagy; Cell death; ER quality control; ERAD; Unfolded protein response.